SO-32 Entrectinib in NTRK fusion-positive gastrointestinal cancers: Updated integrated analysis
Authors: I. Garrido-Laguna, S. Lonardi, L. Bazhenova, M. Peeters, F. Longo, D. Sigal, P. Conkling, F. Duffaud, D. Klingbiel, W. Bordogna, F. Ciardiello
Journal: Annals of Oncology (2022)

Neurotrophic tyrosine receptor kinase ( NTRK ) gene fusions, coding for constitutively active chimeric tyrosine receptor kinase (TRK) proteins, are oncogenic drivers found in a large range of tumour types, including gastrointestinal cancers. Entrectinib is a potent TRK inhibitor with activity in the CNS, that has demonstrated deep and durable responses in patients with a range of NTRK fusion-positive solid tumours from the phase 1/2 ALKA-372-001 (EudraCT 2012-000148-88), STARTRK-1 (NCT02097810) and STARTRK-2 (NCT02568267) clinical trials. In a previous analysis (31 October 2018 data cut-off; n=12), entrectinib was associated with an ORR of 50.0% in patients with NTRK fusion-positive gastrointestinal cancers and had a manageable safety profile. We present updated data for this cohort, with longer follow-up and more patients. Adult patients with locally advanced/metastatic, measurable NTRK fusion-positive gastrointestinal tumours from the ALKA-372-001 and STARTRK-2 clinical trials, and ≥12 months' follow-up from first post-baseline tumour assessment were included in the efficacy analysis. All patients who received ≥1 dose of entrectinib were evaluated for safety. Patients with or without baseline CNS metastases were eligible. Tumour assessments were performed by blinded independent central review (BICR) according to RECIST v1.1 at Week 4 (end of cycle 1), and then every 8 weeks. Primary endpoints: ORR and duration of response (DoR) by BICR; secondary endpoints included progression-free survival (PFS) by BICR, overall survival (OS) and safety assessments. Enrolment cut-off: 31 July 2019; data cut-off: 31 August 2020. The efficacy-evaluable population comprised 16 patients with NTRK fusion-positive gastrointestinal cancers: 10 (63%) had colorectal carcinoma, four (25%) had pancreatic cancer, one (6%) had cholangiocarcinoma and one (6%) had adenocarcinoma of the upper gastrointestinal tract. Median age was 64.5 years (range 31–76); half of the patients were female; 94% had an Eastern Cooperative Oncology Group status 0 or 1; and patients had received zero (n=3; 19%), one (n=4; 25%), two (n=6; 38%) or three (n=3; 19%) prior lines of therapy. None of the patients had investigator-assessed baseline CNS metastases or prior CNS therapy. The median survival follow-up was 30 months. In all patients with NTRK fusion-positive gastrointestinal tumours, ORR was 43.8% (n=7/16; 95% CI 19.8–70.1): the patient with adenocarcinoma of the upper gastrointestinal tract had a complete response; 2/10 patients (20%; 95% CI 2.5–55.6) with colorectal carcinoma, 3/4 patients (75%; 95% CI 19.4–99.4) with pancreatic cancer and the patient with cholangiocarcinoma all had a partial response. Median DoR was 15.1 months (95% CI 9.3–20.0). Median PFS and OS were 7.1 months (95% CI: 2.6–17.5) and 20.4 months (95% CI 12.1–30.7), respectively. In the safety-evaluable population (N=20), median treatment duration was 8.1 months (range 0.5–29.5) and median dose intensity was 93.9% (range 43.3–100.0). Overall, entrectinib was well tolerated; no Grade 4/5 treatment-related adverse events (TRAEs) were reported. TRAEs leading to dose interruption, dose reduction and discontinuation occurred in five (25%), four (20%) and one patient (5%), respectively. In this updated analysis, responses were observed in all NTRK fusion-positive gastrointestinal tumour types, and entrectinib continued to be well tolerated.